This patent invention relates to vitamin D compounds, and more particularly to vitamin D derivatives substituted at the carbon 2 position.
The natural hormone, 1xcex1,25-dihydroxyvitamin D3 and its analog in ergosterol series, i.e. 1xcex1,25-dihydroxyvitamin D2 are known to be highly potent regulators of calcium homeostasis in animals and humans, and more recently their activity in cellular differentiation has been established, Ostrem et al., Proc. Natl. Acad. Sci. USA, 84, 2610 (1987). Many structural analogs of these metabolites have been prepared and tested, including 1xcex1-hydroxyvitamin D3, 1xcex1-hydroxyvitanin D2, various side chain homologated vitamins and fluorinated analogs. Some of these compounds exhibit an interesting separation of activities in cell differentiation and calcium regulation. This difference in activity may be useful in the treatment of a variety of diseases such as renal osteodystrophy, vitamin D-resistant rickets, osteoporosis, psoriasis, and certain malignancies.
Recently, a new class of vitamin D analogs has been discovered, i.e. the so called 19-nor-vitamin D compounds, which are characterized by the replacement of the A-ring exocyclic methylene group (carbon 19), typical of the vitamin D system, by two hydrogen atoms.
Biological testing of such 19-nor-analogs (e.g., 1xcex1,25-dihydroxy-19-nor-vitamin D3) revealed a selective activity profile with high potency in inducing cellular differentiation, and very low calcium mobilizing activity. Thus, these compounds are potentially useful as therapeutic agents for the treatment of malignancies, or the treatment of various skin disorders. Two different methods of synthesis of such 19-nor-vitamin D analogs have been described (Perlman et al., Tetrahedron Lett. 31, 1823 (1990); Perlman et al., Tetrahedron Lett. 32, 7663 (1991), and DeLuca et al., U.S. Pat. No. 5,086,191).
In U.S. Pat. No. 4,666,634, 2xcex2-hydroxy and alkoxy (e.g., ED-71) analogs of 1xcex1,25-dihydroxyvitamin D3 have been described and examined by Chugai group as potential drugs for osteoporosis and as antitumor agents. See also Okano et al., Biochem. Biophys. Res. Commun. 163, 1444 (1989). Other 2-substituted (with hydroxyalkyl, e.g., ED-120, and fluoroalkyl groups) A-ring analogs of 1xcex1,25-dihydroxyvitamin D3 have also been prepared and tested (Miyamoto et al., Chem. Pharm. Bull. 41, 1111 (1993); Nishii et al., Osteoporosis Int. Suppl. 1, 190 (1993); Posner et al., J. Org. Chem. 59 7855 (1994), and J. Org. Chem. 60, 4617 (1995)).
Recently, 2-substituted analogs of 1xcex1,25-dihydroxy-19-norvitamin D3 have also been synthesized, i.e. compounds substituted at 2-position with hydroxy or alkoxy groups (DeLuca et al., U.S. Pat. No. 5,536,713), which exhibit interesting and selective activity profiles. All these studies indicate that binding sites in vitamin D receptors can accommodate different substituents at C-2 in the synthesized vitamin D analogs.
In a continuing effort to explore the 19-nor class of pharmacologically important vitamin D compounds, their analogs which are characterized by the presence of an alkylidene (particularly methylene) substituent at the carbon 2 (C-2), i.e. 2-alkylidene-19-nor-vitamin D compounds, have now been synthesized and tested. Of particular interest are the analogs which are characterized by the transposition of the ring A exocyclic methylene group, present in the normal vitamin D skeleton, from carbon 10 (C-10) to carbon 2 (C-2), i.e. 2-methylene-19-nor-vitamin D compounds. Such vitamin D analogs seemed interesting targets because the relatively small alkylidene (particularly methylene) group at C-2 should not interfere with vitamin D receptor. Moreover, molecular mechanics studies performed on the model 1xcex1-hydroxy-2-methylene-19-nor-vitamins indicate that such molecular modification does not change substantially the conformation of the cyclohexanediol ring A. However, introduction of the 2-methylene group into 19-nor-vitamin D carbon skeleton changes the character of its 1xcex1- and 3xcex2-A-ring hydroxyls. They are both now in the allylic positions, similarly, as 1xcex1-hydroxyl group (crucial for biological activity) in the molecule of the natural hormone, 1xcex1,25-(OH)2D3.
A class of 1xcex1-hydroxylated vitamin D compounds not known heretofore are the 19-nor-vitamin D analogs having an alkylidene (particularly methylene) group at the 2-position, i.e. 2-alkylidene-19-nor-vitamin D compounds, particularly 2-methylene-19-nor-vitamin D compounds. These latter compounds are those in which the A-ring exocyclic methylene group typical of all vitamin D system has been transposed to the carbon 2, i.e. 19-nor-vitamin D analogs having a methylene group at the 2-position.
Structurally these novel analogs are characterized by the general formula I shown below: 
where Y1 and Y2 which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group, R6 and R8, which may be the same or different, are each selected from the group consisting of hydrogen, alkyl, hydroxyalkyl and fluoroalkyl, or, when taken together represent the group xe2x80x94(CH2)Xxe2x80x94 where X is an integer from 2 to 5, and where the group R represents any of the typical side chains known for vitamin D type compounds.
More specifically R can represent a saturated or unsaturated hydrocarbon radical of 1 to 35 carbons, that may be straight-chain, branched or cyclic and that may contain one or more additional substituents, such as hydroxy- or protected-hydroxy groups, fluoro, carbonyl, ester, epoxy, amino or other heteroatomic groups. Preferred side chains of this type are represented by the structure below 
where the stereochemical center (corresponding to C-20 in steroid numbering) may have the R or S configuration, (i.e. either the natural configuration about carbon 20 or the 20-epi configuration), and where Z is selected from Y, xe2x80x94OY, xe2x80x94CH2OY, xe2x80x94Cxe2x89xa1CY, CHxe2x95x90CHY, and xe2x80x94CH2CH2CHxe2x95x90CR3R4, where the double bond may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, xe2x80x94COR5 and a radical of the structure: 
where m and n, independently, represent the integers from 0 to 5, where R1 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R2, R3, and R4, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R1 and R2, taken together, represent an oxo group, or an alkylidene group, xe2x95x90CR2R3, or the group xe2x80x94(CH2)pxe2x80x94, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group xe2x80x94(CH2)qxe2x80x94, where q is an integer from 2 to 5, and where R5 represents hydrogen, hydroxy, protected hydroxy, C1-5 alkyl or R7 where R7 represents C1-5 alkyl, and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups xe2x80x94CH(CH3)xe2x80x94, xe2x80x94CH(R3)xe2x80x94, or xe2x80x94CH(R2)xe2x80x94 at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.
The wavy line to the methyl substituent at C-20 indicates that carbon 20 may have either the R or S configuration.
Specific important examples of side chains with natural 20R-configuration are the structures represented by formulas (a), b), (c), (d) and (e) below. i.e. the side chain as it occurs in 25-hydroxyvitamin D3 (a); vitamin D3 (b); 25-hydroxyvitamin D2 (c); vitamin D2 (d); and the C-24 epimer of 25-hydroxyvitamin D2 (e): 
Specific important examples of side chains with the unnatural 20(S) (also referred to as the 20-epi) configuration are the structures represented by formulas (f), (g), (h), and (i) below: 
The above novel compounds exhibit a desired, and highly advantageous, pattern of biological activity. These compounds are characterized by relatively high intestinal calcium transport activity, as compared to that of 1xcex1,25-dihydroxyvitamiin D3, while also exhibiting relatively high activity, as compared to a 1xcex1,25-dihydroxyvitamin D3, in their ability to mobilize calcium from bone. Hence, these compounds are highly specific in their calcemic activity. Their preferential activity on mobilizing calcium from bone and either high or normal intestinal calcium transport activity allows the in vivo administration of these compounds for the treatment of metabolic bone diseases where bone loss is a major concern. Because of their preferential calcemic activity on bone, these compounds would be preferred therapeutic agents for the treatment of diseases where bone formation is desired, such as osteoporosis, especially low bone turnover osteoporsis, steroid induced osteoporosis, senile osteoporosis or postmenopausal osteoporosis, as well as osteomalacia and renal osteodystrophy. The treatment may be transdermal, oral or parenteral. The compounds may be present in a composition in an amount from about 0.1 xcexc/gm to about 50 xcexcg/gm of the composition, and may be administered in dosages of from about 0.1 xcexcg/day to about 50 xcexcg/day.
The compounds of the invention are also especially suited for treatment and prophylaxis of human disorders which are characterized by an imbalance in the immune system, e.g. in autoimmune diseases, including multiple sclerosis, diabetes mellitus, host versus graft reaction, and rejection of transplants; and additionally for the treatment of inflammatory diseases, such as rheumatoid arthritis and asthma, as well as the improvement of bone fracture healing and improved bone grafts. Acne, alopecia, skin conditions such as dry skin (lack of dermal hydration), undue skin slackness (insufficient skin firmness), insufficient sebum secretion and wrinkles, and hypertension are other conditions which may be treated with the compounds of the invention.
The above compounds are also characterized by high cell differentiation activity. Thus, these compounds also provide therapeutic agents for the treatment of psoriasis, or as an anti-cancer agent, especially against leukemia, colon cancer, breast cancer and prostate cancer. The compounds may be present in a composition to treat psoriasis in an amount from about 0.01 xcexcg/gm to about 100 xcexcg/gm of the composition, and may be administered topically, transdermally, orally or parenterally in dosages of from about 0.01 xcexcg/day to about 100 xcexcg/day.
This invention also provides novel intermediate compounds formed during the synthesis of the end products. Structurally, these novel intermediates are characterized by the general formulae V, VI, VII, VIII, IX and X below where Y1, Y2, R6 and R8 are as previously defined herein. 
This invention also provides a novel synthesis for the production of the end products of structure I.